1. Field of the Invention
The present invention relates to methods of reducing the side-effects associated with administering oxygen-carrying proteins to mammals. In particular, the present invention relates to methods of reducing the side-effects associated with administering hemoglobin-containing compositions to mammals in need thereof.
2. Description of Related Art
Over the years, several substances have been suggested as potential replacements for the naturally-occurring hemoglobin-based oxygen transport systems of mammals. For example, the scientific literature often includes reports of various blood substitutes such as perfluorocarbon emulsions, recombinant hemoglobin products, cross-linked hemoglobin compositions which include human or bovine hemoglobins, ultra-purified bovine hemoglobin compositions and polyethylene glycol-hemoglobin conjugates.
Not unexpectedly, there have been shortcomings associated with many of the products under consideration. For example, early perfluorocarbon emulsions have not been favorably accepted due to drawbacks associated with product preparation before use (dilution and mixing), detergent based-emulsifying agents and the requirement that the patient breathe 95% oxygen during use. In addition, the compounds have a short circulating life, and are known to accumulate in the liver and spleen. The product is not metabolized per se but rather is exhaled as a gas over time through the lungs. Given the prolonged organ residence time, toxicities including thrombocytopenia have raised concerns regarding multiple doses and tissue loading.
In addition, the (in vivo) circulating life of some blood substitutes has been less than that which is believed to be therapeutically optimal. Some solutions have been offered to address this shortcoming. For example, inter- and/or intra-molecular cross-linking hemoglobin molecules or covalently attaching polymers such as PEG have been suggested as means for extending the circulating life of the oxygen carriers. See also U.S. Pat. Nos. 5,234,903, 5,386,014, 5,312,808 and 5,478,805, the contents of which are each incorporated herein by reference.
Some proposed products have been associated with significant side-effects after intravenous administration. Side-effects, if significant, substantially reduce the commercial and therapeutic value of these products. For example, some recombinant hemoglobin products undergoing clinical evaluation were found to unexpectedly cause alpha-adrenergic, acetylcholine-mediated, possible endothelin and/or nitric oxide-induced side effects in humans after administration. These side-effects are believed to be related to not only the dose of the recombinant hemoglobin administered but also the formulation of the recombinant hemoglobin and volume administered. Current recombinant hemoglobin formulations under consideration, therefore, are of limited usefulness especially in situations where large amounts of the recombinant protein are required for treatment. Large volume administration of such preparations for replacement of blood loss due to trauma or transfusions are likely to result in one or more side-effects.
It would be highly desirable to provide a method of allowing oxygen-carrying proteins to be delivered to patients in relatively large volumes without significantly incurring the types of side-effects which heretofore were observed. The present invention addresses this issue and is described below.